This application is a 371 of PCT/JP00/06673 filed Sep. 27, 2000, now Ser. No. WO 01/23350.
The present invention relates to thioalkylamine derivatives represented by general formula (I) which are useful as intermediates of medicines, agrochemicals, chemical products, etc., and a process for production of the derivatives.
Thioalkylamine derivatives are useful as intermediates for synthesis of agrochemicals, medicines, chemical products, etc. or starting materials for them. When used in agrochemicals, the derivatives are useful compounds as, for example, starting compounds for the agricultural and horticultural insecticide disclosed in Japanese Patent Application No. 11-338715 filed by the same applicant as the present applicant.
Thioalkylamines can be classified into thiols and sulfides according to chemical structure. As a process for producing any of the thiols and the sulfides, the following processes have been reported.
(1) A process in which a thiol is produced by hydrolyzing a thiazoline or thiazolidinone derivative (for example, J. Med. Chem., 1965, 8, 762; JP-A-59-231064; Bull. Soc. Chim. Fr. 1967, 3637; and Z. Naturforsch., B: Chem. Sci. 1987, 42, 348). (2) A process in which a sulfide is produced by reacting an oxazoline or oxazolidinone derivative with a thiol (for example, J. Org. Chem., 1992, 57,6257; and J. Med. Chem., 1984, 27, 1354). (3) A process in which a sulfide or a thiol is produced by reacting an aziridine with a sulfur compound such as a mercaptan (for example, Tetrahedron, 1992, 48, 2359; J. Am. Chem. Soc., 1986, 108,.3811; Inorg. Chem., 1984, 23, 3404; and Tetrahedron Lett., 1983, 24, 2131). (4) A process in which a sulfide is produced by hydrolyzing an amide obtained by reacting an amino alcohol with a mercaptan in a carboxylic acid (for example, Neth. Appl. 6, 404, 644). (5) A process in which a thiol is produced by reacting an amino alcohol sulfate ester with ammonium hydrogensulfide (for example, Journal of Chemical Society of Japan, 1979, 149). (6) A process in which a thioalkyl alcohol is converted to a thioalkylamine by Ritter reaction and hydrolysis (for example, Ger. Offen. 2,045,905).
A desired compound in the present invention is a sulfide as a thioalkylamine. Therefore, of the above prior arts, the production processes (2), (3), (4) and (6) are closely concerned with the desired compound. However, the process (2) involves, for example, the following problem: it requires a hydrolysis step because the product is obtained as an amide, and the reaction does not take place if a substituent such as an alkyl group is present in the oxazolidine ring of the starting compound. This process is also disadvantageous in that only an aromatic sulfide can be produced owing to the acidity of a mercapto group. The process (3) is not suitable for industrial adoption from the viewpoint of safety and facilities because the aziridine whose toxicity tends to affect the health of production workers is used after its production and isolation. The process (4) is disadvantageous, for example, in that the product is limited to a thiol because the reaction is carried out with heating under pressure for a long period of time. Moreover, this process is disadvantageous, for example, in that like the process (2), it requires hydrolysis because the product is obtained as an amide. The process (6) is disadvantageous, for example, in that an excess of prussic acid is used which is very toxic and requires great care in handling and after-treatment, or that the hydrolysis is not easy when an easily handleable nitrile is used.
Although the processes (1) and (5) are production processes of a thiol and are not directly concerned with a process for producing a sulfide intended according to the present invention, they involve the following problems. That is, the process (1) is industrially disadvantageous from the viewpoint of the number of steps and yield because the thiazoline or thiazolidinone derivative should be produced. The process (5) is industrially disadvantageous in that it entails high cost in view of facilities and production efficiency because the reaction is carried out in a sealed tube for a long period of time.
The present invention avoids, for example, the following various problems in prior arts: a reaction is carried out at a high temperature and a high pressure for a long period of time; an additional step such as hydrolysis is needed; there are various restrictions on introducible substituents; and the toxicity of a starting material used and the like is so high that safety and facilities required for handling and after-treatment of the staring material and the like cost a great deal. Thus, the present invention provides a production process which is simple and short, can be generally adopted, can be safely practiced, and is economically advantageous.
In order to solve the above problems and develop a novel process for producing a thioalkylamine, the present inventors earnestly investigated and consequently found that the above object can be achieved by producing a sulfate ester represented by general formula (III) by the reaction of an amino alcohol represented by general formula (II) with sulfuric acid, and reacting the sulfate ester with a mercaptan under basic conditions, whereby the present invention has been accomplished.
The present invention relates to a thioalkylamine derivative represented by general formula (I): 
wherein each of R1 and R2, which may be the same or different, is a hydrogen atom; a (C1-C4)alkyl group; a (C3-C8)cycloalkyl group; a (C3-C8)cycloalkyl(C1-C4)alkyl group; a hydroxy-(C1-C4)alkyl group; a phenyl group; a substituted phenyl group having 1 to 5 substituents which may be the same or different and each of the substituents is selected from a halogen atom, a cyano group, a nitro group, a (C1-C4)alkyl group, a halo(C1-C4)alkyl group, a (C3-C8)cycloalkyl group, a (C1-C4)alkoxy group, a halo(C1-C4)alkoxy group, a (C1-C4)alkylthio group, a halo(C1-C4)alkylthio group, a (C1-C4)alkylsulfinyl group, a halo(C1-C4)alkylsulfinyl group, a (C1-C4)alkylsulfonyl group, a halo(C1-C4)alkylsulfonyl group, a carboxyl group, a (C1-C4)alkoxycarbonyl group, a (C1-C4)alkoxy(C1-C4)alkyl group, R7xe2x80x94C(xe2x95x90O)xe2x80x94 (wherein R7 is a (C1-C4)alkyl group, a halo(C1-C4)alkyl group, a phenyl group or a phenoxy group), an amino group, and a substituted amino group having one or two substituents which may be the same or different and are selected from (C1-C4)alkyl groups; a substituted phenyl group having as the substituent a (C3-C4)alkylene group or a (C1-C2)alkylenedioxy group, which forms a ring together with a pair of adjacent carbon atoms in the benzene ring; a phenyl(C1-C4)alkyl group; or a substituted phenyl(C1-C4)alkyl group having on the ring 1 to 5 substituents which may be the same or different and each of the substituents is selected from a halogen atom, a cyano group, a nitro group, a (C1-C4)alkyl group, a halo(C1-C4)alkyl group, a (C3-C8)cycloalkyl group, a (C1-C4)alkoxy group, a halo(C1-C4)alkoxy group, a (C1-C4)alkylthio group, a halo(C1-C4)alkylthio group, a (C1-C4)alkylsulfinyl group, a halo(C1-C4)alkylsulfinyl group, a (C1-C4)alkylsulfonyl group and a halo(C1-C4)alkylsulfonyl group; R1 and R2 may form a (C2-C5)alkylene group by binding to each other; R1 and R3 or R5 may form a (C3-C5)alkylene group by binding to each other,
each of R3 and R4, which may be the same or different, is a hydrogen atom or a (C1-C4)alkyl group; R3 and R4 may form a (C4-C6)alkylene group by binding to each other; R3 and R5 may form a (C2-C4)alkylene group by binding to each other,
each of R5 and R6, which may be the same or different, is a hydrogen atom; a (C1-C4)alkyl group; a phenyl group; a substituted phenyl group having 1 to 5 substituents which may be the same or different and each of the substituents is selected from a halogen atom, a cyano group, a nitro group, a (C1-C4)alkyl group, a halo(C1-C4)alkyl group, a (C3-C8)cycloalkyl group, a (C1-C4)alkoxy group, a halo(C1-C4)alkoxy group, a (C1-C4)alkylthio group, a halo(C1-C4)alkylthio group, a (C1-C4)alkylsulfinyl group, a halo(C1-C4)alkylsulfinyl group, a (C1-C4)alkylsulfonyl group and a halo(C1-C4)alkylsulfonyl group; a phenyl(C1-C4)alkyl group; or a substituted phenyl(C1-C4)alkyl group having on the ring 1 to 5 substituents which may be the same or different and each of the substituents is selected from a halogen atom, a cyano group, a nitro group, a (C1-C4)alkyl group, a halo(C1-C4)alkyl group, a (C3-C8)cycloalkyl group, a (C1-C4)alkoxy group, a halo(C1-C4)alkoxy group, a (C1-C4)alkylthio group, a halo(C1-C4)alkylthio group, a (C1-C4)alkylsulfinyl group, a halo(C1-C4)alkylsulfinyl group, a (C1-C4)alkylsulfonyl group and a halo(C1-C4)alkylsulfonyl group; R5 and R6 may form a (C4-C6)alkylene group by binding to each other, and
R is a (C1-C12)alkyl group; a (C3-C8)cycloalkyl group; a (C3-C8)cycloalkyl(C1-C4)alkyl group; a phenyl group; a substituted phenyl group having 1 to 5 substituents which may be the same or different and each of the substituents is selected from a halogen atom, a (C1-C6)alkyl group, a halo(C1-C3)alkyl group, a (C3-C8)cycloalkyl group, a (C1-C4)alkoxy group and a halo(C1-C4)alkoxy group; a phenyl(C1-C4)alkyl group; a substituted phenyl(C1-C4)alkyl group having on the ring 1 to 5 substituents which may be the same or different and each of the substituents is selected from a halogen atom and a (C1-C4)alkyl group; a naphthyl group; an aromatic heterocyclic group; or a substituted aromatic heterocyclic group having one or more substituents which may be the same or different and each of the substituents is selected from a halogen atom, a (C1-C4)alkyl group, a (C1-C4)alkoxy group, a phenyl group, and a substituted phenyl group having 1 to 5 substituents which may be the same or different and each of the substituents is selected from a halogen atom and a (C1-C4)alkyl group,
provided that:
(1) when R1, R2, R3, R4, R5 and R6 are hydrogen atoms at the same time, then R is not a (C1-C6)alkyl group, phenyl group and aromatic heterocyclic group of 2-furyl group, 2-thienyl group, 2-thiazolyl group, 2-imidazolyl group, 2-pyridyl group and 2-pyrimidinyl group.
(2) when R1, R2, R3, R4 and R6 are hydrogen atoms at the same time and R5 is a (C1-C4)alkyl group or a phenyl group, then R is not a (C1-C4)alkyl group, phenyl group and aromatic heterocyclic group of pyridyl group and pyrimidinyl group.
(3) when R1, R2, R3 and R4 are hydrogen atoms at the same time and each of R5 and R6 is a (C1-C4)alkyl group or a phenyl group, then R is not a (C1-C5)alkyl group, phenyl group and aromatic heterocyclic group of triazolyl group, tetrazolyl group, 1,2,3-thiadiazolyl group, pyridyl group, 2-pyrimidinyl group and pyrazinyl group,
(4) when R2, R3, R4, R5 and R6 are hydrogen atoms at the same time and R is a phenyl group, then R1 is not a (C1-C4)alkyl group and phenyl group,
(5) when R2, R3, R4, R5 and R6 are hydrogen atoms at the same time and R1 is a methyl group, then R is not a methyl group and aromatic heterocyclic group of 2-benzothiazolyl group,
(6) when R2, R3, R4 and R6 are hydrogen atoms at the same time, R1 is a methyl group and R is a methyl group, then R5 is not a (C1-C3)alkyl group and phenyl group,
(7) when R2, R3, R4, R5 and R6 are hydrogen atoms at the same time and R1 is an ethyl group, then R is not an aromatic heterocyclic group of 2-indolyl group,
(8) when R2, R3, R4 and R5 are hydrogen atoms at the same time, R6 is a phenyl group and R1 is a methyl group, then R is not a methyl group and t-butyl group,
(9) when R2, R3, R4 and R5 are hydrogen atoms at the same time, R6 is a phenyl group and R1 is a propyl group, then R is not a methyl group and phenyl group,
(10) when R2, R3 and R4 are hydrogen atoms at the same time, each of R5 and R6 is a methyl group, a propyl group or a phenyl group and R1 is a methyl group, then R is not a methyl group, t-butyl group and phenyl group,
(11) when R2, R3 and R4 are hydrogen atoms at the same time, R5 and R6 are methyl groups at the same time and R1 is a propyl group, then R is not an ethyl group and phenyl group,
(12) when R2, R3, R4 and R5 are hydrogen atoms at the same time, R1 is a phenyl group and R is a methyl group or a phenyl group, then R6 is not a methyl group, n-propyl group and phenyl group,
(13) when R2, R3, R4 and R5 are hydrogen atoms at the same time, R1 is a phenyl group and R is a butyl group, then R6 is not a hydrogen atom and methyl group,
(14) when R2, R3 and R4 are hydrogen atoms at the same time, R5 and R6 are methyl groups at the same time and R1 is a phenyl group, then R is not a methyl group and phenyl group,
(15) when R1, R2, R4, R5 and R6 are hydrogen atoms at the same time and R3 is a methyl group, then R is not a methyl group and phenyl group,
(16) when R1, R2 and R4 are hydrogen atoms at the same time, R3 is a (C1-C4)alkyl group and each of R5 and R6 is a methyl group, an ethyl group or a phenyl group, then R is not a (C1-C3)alkyl group and phenyl group,
(17) when R3, R4, R5 and R6 are hydrogen atoms at the same time and R1 and R2 are methyl groups at the same time, then R is not a methyl group, ethyl group and phenyl group,
(18) when R3, R4, R5 and R6 are hydrogen atoms at the same time and R1 and R2 are n-propyl groups at the same time, then R is not a methyl group,
(19) when R3, R4, R5 and R6 are hydrogen atoms at the same time, R1 is an ethyl group and R2 is an n-butyl group, then R is not an aromatic heterocyclic group of 2-thienyl group,
(20) when R3, R4 and R6 are hydrogen atoms at the same time, R1 and R2 are methyl groups at the same time and R5 is a phenyl group, then R is not a phenyl group,
(21) when R3 and R4 are hydrogen atoms at the same time and R1, R2, R5 and R6 are methyl groups at the same time, then R is not a methyl group,
(22) when R1, R2, R5 and R6 are hydrogen atoms at the same time and R3 and R4 are methyl groups at the same time, then R is not a methyl group,
(23) when R1, R2 and R6 are hydrogen atoms at the same time, R3 and R4 are methyl groups at the same time and R5 is a t-butyl group, then R is not a phenyl group,
(24) when R1 and R2 are hydrogen atoms at the same time and R3, R4, R5 and R6 are methyl groups at the same time, then R is not a methyl group,
(25) when R2, R4, R5 and R6 are hydrogen atoms at the same time, R1 is a methyl group, an ethyl group or a phenyl group and R3 is a methyl group, then R is not a methyl group and phenyl group,
(26) when R2, R4, R5 and R6 are hydrogen atoms at the same time, R1 is a (C1-C4)alkyl group and R3 is an n-butyl group, then R is not a methyl group,
(27) when R2, R4 and R6 are hydrogen atoms at the same time, R1 is an ethyl group and R3 and Rare methyl groups at the same time, then R5 is not a methyl group and ethyl group,
(28) when R2 and R4 are hydrogen atoms at the same time, each of R1 and R6 is a methyl group or an ethyl group and R3 and R5 are methyl groups at the same time, then R is not a methyl group and phenyl group, and
(29) when R1 is an isopropyl group, R2, R5 and R6 are hydrogen atoms at the same time and R3 and R4 are methyl groups at the same time, then R is not a methyl group. Furthermore, the present invention relates to a novel process for producing a thioalkylamine derivative represented by general formula (I): 
(wherein R1, R2, R3, R4, R5, R6 and R are as defined below) and including well-known thioalkylamine derivatives, which is characterized by reacting sulfuric acid with an amino alcohol represented by general formula (II): 
(wherein each of R1 and R2, which may be the same or different, is a hydrogen atom; a (C1-C4)alkyl group; a (C3-C8)cycloalkyl group; a (C3-C8)cycloalkyl(C1-C4)alkyl group; a hydroxy(C1-C4)alkyl group; a phenyl group; a substituted phenyl group having 1 to 5 substituents which may be the same or different and each of the substituents is selected from a halogen atom, a cyano group, a nitro group, a (C1-C4)alkyl group, a halo(C1-C4)alkyl group, a (C3-C8)cycloalkyl group, a (C1-C4)alkoxy group, a halo(C1-C4)alkoxy group, a (C1-C4)alkylthio group, a halo(C1-C4)alkylthio group, a (C1-C4)alkylsulfinyl group, a halo(C1-C4)alkylsulfinyl group, a (C1-C4)alkylsulfonyl group, a halo(C1-C4)alkylsulfonyl group, a carboxyl group, a (C1-C4)alkoxycarbonyl group, a (C1-C4)alkoxy(C1-C4)alkyl group, R7xe2x80x94C(xe2x95x90O)xe2x80x94 (wherein R7 is a (C1-C4)alkyl group, a halo(C1-C4)alkyl group, a phenyl group or a phenoxy group), an amino group, and a substituted amino group having one or two substituents which may be the same or different and are selected from (C1-C4)alkyl groups; a substituted phenyl group having as the substituent a (C3-C4)alkylene group or a (C1-C2)alkylenedioxy group, which forms a ring together with a pair of adjacent carbon atoms in the benzene ring; a phenyl(C1-C4)alkyl group; or a substituted phenyl(C1-C4)alkyl group having on the ring 1 to 5 substituents which may be the same or different and each of the substituents is selected from a halogen atom, a cyano group, a nitro group, a (C1-C4)alkyl group, a halo(C1-C4)alkyl group, a (C3-C8)cycloalkyl group, a (C1-C4)alkoxy group, a halo(C1-C4)alkoxy group, a (C1-C4)alkylthio group, a halo(C1-C4)alkylthio group, a (C1-C4)alkylsulfinyl group, a halo(C1-C4)alkylsulfinyl group, a (C1-C4)alkylsulfonyl group and a halo(C1-C4)alkylsulfonyl group; R1 and R2 may form a (C2-C4)alkylene group by binding to each other; R1 and R3 or R5 may form a (C3-C5)alkylene group by binding to each other,
each of R3 and R4, which may be the same or different, is a hydrogen atom or a (C1-C4)alkyl group; R3 and R4 may form a (C4-C6)alkylene group by binding to each other; R3 and R5 may form a (C2-C4)alkylene group by binding to each other,
each of R5 and R6, which may be the same or different, is a hydrogen atom; a (C1-C4)alkyl group; a phenyl group; a substituted phenyl group having 1 to 5 substituents which may be the same or different and each of the substituents is selected from a halogen atom, a cyano group, a nitro group, a (C1-C4)alkyl group, a halo(C1-C4)alkyl group, a (C3-C8)cycloalkyl group, a (C1-C4)alkoxy group, a halo(C1-C4)alkoxy group, a (C1-C4)alkylthio group, a halo(C1-C4)alkylthio group, a (C1-C4)alkylsulfinyl group, a halo(C1-C4)alkylsulfinyl group, a (C1-C4)alkylsulfonyl group and a halo(C1-C4)alkylsulfonyl group; a phenyl(C1-C4)alkyl group; or a substituted phenyl(C1-C4)alkyl group having on the ring 1 to 5 substituents which may be the same or different and each of the substituents is selected from a halogen atom, a cyano group, a nitro group, a (C1-C4)alkyl group, a halo(C1-C4)alkyl group, a (C3-C8)cycloalkyl group, a (C1-C4)alkoxy group, a halo(C1-C4)alkoxy group, a (C1-C4)alkylthio group, a halo(C1-C4)alkylthio group, a (C1-C4)alkylsulfinyl group, a halo(C1-C4)alkylsulfinyl group, a (C1-C4)alkylsulfonyl group and a halo(C1-C4)alkylsulfonyl group; and R5 and R6 may form a (C4-C6)alkylene group by binding to each other) to obtain a sulfate ester represented by general formula (III): 
(wherein R1, R2, R3, R4, R5 and R6 are as defined above), and reacting the sulfate ester, after or without isolation, with a mercaptan represented by general formula (IV):
RSMxe2x80x83xe2x80x83(IV)
(wherein R is a (C1-C12)alkyl group; a (C3-C8)cycloalkyl group; a (C3-C8)cycloalkyl(C1-C4)alkyl group; a phenyl group; a substituted phenyl group having 1 to 5 substituents which may be the same or different and each of the substituents is selected from a halogen atom, a (C1-C6)alkyl group, a halo(C1-C3)alkyl group, a (C3-C,)cycloalkyl group, a (C1-C4)alkoxy group and a halo(C1-C4)alkoxy group; a phenyl(C1-C4)alkyl group; a substituted phenyl(C1-C4)alkyl group having on the ring 1 to 5 substituents which may be the same or different and each of the substituents is selected from a halogen atom and a (C1-C4)alkyl group; a naphthyl group; an aromatic heterocyclic group; or a substituted aromatic heterocyclic group having one or more substituents which may be the same or different and each of the substituents is selected from a halogen atom, a (C1-C4)alkyl group, a (C1-C4)alkoxy group, a phenyl group and a substituted phenyl group having 1 to 5 substituents which may be the same or different and each of the substituents is selected from a halogen atom and a (C1-C4)alkyl group, and M is a hydrogen atom, an ammonium group or an alkali metal atom).
By the production process of the present invention, a thioalkylamine can be produced safely without directly handling a very toxic reagent, intermediate or the like. Moreover, the production process permits industrially advantageous production of said thioalkylamine without using a special reactor or the like.
Examples of the substituents in the present invention are given below. In the abbreviated representation of the chemical formulas in the present invention, xe2x80x9ci-xe2x80x9d is a prefix for xe2x80x9cisoxe2x80x9d, xe2x80x9cs-xe2x80x9d is a prefix for xe2x80x9csecondaryxe2x80x9d, and xe2x80x9ct-xe2x80x9d is a prefix for xe2x80x9ctertiaryxe2x80x9d.
In the definition of the substituents of the thioalkylamine derivative represented by general formula (I) of the present invention, the term xe2x80x9chalogen atomxe2x80x9d means a chlorine atom, a bromine atom, an iodine atom or a fluorine atom. The term xe2x80x9c(C1-C4)alkylxe2x80x9d or xe2x80x9c(C1-C6)alkyl,xe2x80x9d means a linear or branched alkyl group of 1 to 4 carbon atoms or 1 to 6 carbon atoms, respectively, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl or the like. The term xe2x80x9chalo(C1-C4)alkylxe2x80x9d or xe2x80x9chalo(C1-C6)alkylxe2x80x9d means a substituted linear or branched alkyl group of 1 to 4 carbon atoms or 1 to 6 carbon atoms, respectively, having as the substituent(s) one or more halogen atoms which may be the same or different. The term xe2x80x9c(C3-C6)alkylenexe2x80x9d means a linear or branched alkylene group of 3 to 6 carbon atoms, such as propylene, trimethylene, dimethylmethylene, tetramethylene, methyltrimethylene, dimethylethylene or the like.
The aromatic heterocyclic group includes, for example, furan, thiophene, pyrrole, oxazole, oxazoline, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine and triazine. In any of these groups, one or more nitrogen atoms in the molecule may be oxidized. In addition, benzo derivatives of these groups may also be used. The xe2x80x9cbenzo derivativesxe2x80x9d include, for example, benzofuran, isobenzofuran, 1-benzothiophene, 2-benzothiophene, indole, isoindole, 1,2-benzothiazole, 1,3-benzothiazole, 2,1- benzothiazole, indazole, benzimidazole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, phthalazine, 1,2,3-benzothiadiazole, benzotriazole, benzoxazine, benzothiazine, benzopyridazine, 1-oxo-4-azanaphthalene and 1-thia-4-azanaphthalene. The substitution position(s) in the benzo derivatives is not particularly limited.
The thioalkylamine derivatives of general formula (I) of the present invention can be produced, for example, by the production process schematically shown below: 
wherein R1, R2, R3, R4, R5, R6 and R are as defined above.
The thioalkylamine of general formula (I) can be produced by reacting an amino alcohol of general formula (II) with sulfuric acid in the presence of an inert solvent to produce a sulfate ester of general formula (III), and reacting the sulfate ester with a mercaptan of general formula (IV) in the presence of a base and an inert solvent after or without isolating the sulfate ester.
1. General Formula (II)xe2x86x92General Formula (III)
In the case of this reaction, the desired compound can be produced by distilling off the water from a mixed aqueous solution of the amino alcohol of general formula (II) and sulfuric acid. The desired compound can be produced by the process described, for example, in Organic Syntheses Collective Volume 3, 148 and J. Am. Chem. Soc., 1959, 81, 4689.
As the amino alcohol as staring material in the reaction, there can be used, for example, ethanolamine, 2-amino-1-propanol, 2-amino-2-methyl-1-propanol, 2-amino-1-butanol, 2-amino-1-pentanol, 2-amino-3-methyl-1-butanol, 2-amino-1-hexanol, isoleucinol, leucinol and 1-amino-1-cyclopentanemethanol.
In the reaction, an azeotropic dehydrating solvent is preferably used in order to remove continuously the water produced in the reaction system. As the azeotropic dehydrating solvent, there can be used, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as chloroform, dichloroethane, trichloroethane, dichloropropane, trichloroethylene, tetrachloroethylene, fluorobenzene, chlorobenzene, dichlorobenzene, etc.; nitrated hydrocarbons such as nitromethane, nitroethane, nitropropane, etc.; nitrile type hydrocarbons such as acetonitrile, propionitrile, butyronitrile, etc.; polyether type hydrocarbons such as diglyme, propylene glycol dimethyl ether, etc.; and carbonic acid esters such as diethyl carbonate, etc.
The amount of sulfuric acid used may be 1 equivalent or more per equivalent of the amino alcohol of general formula (II). The reaction temperature may be the boiling point of the inert solvent used. When an azeotropic dehydrating solvent is used, the reaction temperature may be any temperature so long as it permits azeotropic dehydration. Although the reaction time is varied depending on the scale of reaction, the reaction may be carried out in the range of 1 to 24 hours, preferably 1 to 10 hours.
The sulfate ester of general formula (III) may be isolated and purified if necessary, or it may be used as it is in the subsequent step without isolation and purification.
2. General Formula (III)xe2x86x92General Formula (I)
As the mercaptan of general formula (IV) used in this reaction, there can be used, for example, methylmercaptan, ethylmercaptan, propylmercaptan, isopropylmercaptan, butylmercaptan, hexylmercaptan, cyclohexylmercaptan, octylmercaptan, decylmercaptan, dodecylmercaptan, thiophenol, thiocresol, ethylthiophenol, isopropylthiophenol, t-butylthiophenol, dimethylthiophenol, fluorothiophenol, chlorothiophenol, bromothiophenol, dichlorobenzenethiol, methoxybenzenethiol, benzylmercaptan, chlorobenzylmercaptan, t-butylbenzylmercaptan, naphthalenethiol, mercaptopyridine, 2-mercaptopyridine N-oxide, mercaptopyrimidine, dimethylmercaptopyrimidine, dimethoxymercaptopyrimidine, methylfuranthiol, furfurylmercaptan, mercaptoimidazole, 2-mercapto-1-methylimidazole, 1,2,4-triazole-3-thiol, 4-methyl-1,2,4-triazole-3-thiol, 5-methyl-1,3,4-thiadiazole-2-thiol, 4-methyl-1,2,3-thiadiazole-5-thiol and 4-t-butyl-1,2,3-thiadiazole-5-thiol. There can also be used salts of these compounds, such as alkali metal salts (e.g. sodium salts, potassium salts and lithium salts), ammonium salts, etc. As to the amount of the mercaptan used, the reaction may be carried out by choosing the amount in the range of 1 to 10 equivalents, preferably 1 to 2 equivalents, per equivalent of the sulfate ester of general formula (III).
As the base, there can be used inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. The amount of the base used ranges from 1 to 5 equivalents, preferably 1 to 3 equivalents, per equivalent of the sulfate ester of general formula (III).
As the inert solvent, there can be used, for example, either water or a mixed solvent of water and an organic solvent. As the organic solvent, there can be used, for example, alcohols such as methanol, ethanol, propanol, isopropanol, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as chloroform, dichloroethane, trichloroethane, dichloropropane, trichloroethylene, tetrachloroethylene, fluorobenzene, chlorobenzene, dichlorobenzene, etc.; nitrated hydrocarbons such as nitromethane, nitroethane, nitropropane, etc.; nitrile type hydrocarbons such as acetonitrile, propionitrile, butyronitrile, etc.; polyether type hydrocarbons such as diglyme, etc.; and carbonic acid esters such as diethyl carbonate, etc. The alcohols such as methanol, ethanol, etc. may be used singly or as a mixture of two or more thereof.
The reaction temperature is 50 to 150xc2x0 C., preferably 65 to 100xc2x0 C. Although varied depending on the scale of reaction, the reaction time ranges from several minutes to 24 hours, preferably from 1 to 10 hours.
After completion of the reaction, the desired compound is isolated from the reaction system containing the desired compound by a conventional method, and if necessary, purified, whereby the thioalkylamine derivative of general formula (I) can be produced.
When the reactions 1 and 2 are carried out in succession, the reaction 2 may be carried out by adding water, the base and the mercaptan to the reaction system without isolating the sulfate ester. As to the amount of the base used, when sulfuric acid is used in an amount of more than 1 equivalent, the amount of the base should be increased by an amount corresponding to the surplus sulfuric acid. When a mixed solvent of water or an alcohol and an organic solvent is used, the mixing ratio may be properly chosen so that the amount of water or the alcohol may be sufficient to dissolve the sulfate ester and that when a solid mercaptan is used, the amount of the organic solvent is sufficient to dissolve this mercaptan. When the mercaptan is liquid, the reaction 2 can be carried out without using an organic solvent, though it is preferable to use an organic solvent properly when a mercaptan having a low boiling point is used.